The present invention relates to pharmaceutical compositions in liquid form which are suitable for the delivery of active ingredients to the posterior segment of an eye.
Today, ophthalmic diseases affecting tissues of the posterior segment of the eye are responsible for most cases of irreversible blindness worldwide. These include conditions such as glaucoma, age-related macular degeneration, diabetic retinopathy, and retinitis pigmentosa.
Glaucoma is a disease characterised by severe damage to the optic nerve leading to progressive, potentially irreversible loss of vision. The damage involves loss of retinal ganglion cells in a characteristic pattern. Glaucoma is often, but not always, associated with increased ocular pressure. According to WHO estimates, the disease contributed to more than 12% of all causes for blindness globally in 2002.
Age-related macular degeneration accounted for 8.7% of blindness worldwide in 2002. It is a condition involving damage to the retina in a pattern that leads to a loss of vision in the centre of the visual field, also known as the macula.
Diabetic retinopathy is an ocular condition which affects up to 80% of all patients who have had diabetes for 10 years or more, and accounts for about 5% of the incidence of blindness worldwide. The retinopathy is the result of microvascular retinal changes. A hyperglycaemia-induced death of ocular pericytes leads to capillary wall damage and potentially oedema, such as macular oedema. In the absence of treatment, blurred vision and eventually blindness may develop as a result.
Retinitis pigmentosa describes a group of ophthalmic diseases which have a genetic origin, and which are characterised by progressive retinal dystrophy, i. e. a degeneration of the photoreceptors or the retinal pigment epithelium resulting in a loss of vision. The condition often becomes manifest in the form of impaired dark adaptation or nyctalopia, often followed by reduction of the peripheral visual field. At a progressed stage of the disease, it may involve the loss of central vision.
For at least some of the diseases affecting the tissues of the posterior segment of the eye, it may be possible to slow their progression, reduce the severity of symptoms, or even substantially control the condition by pharmacotherapy. For example, in the case of glaucoma, several classes of active agents have been used with significant success, including prostaglandin analogs (such as latanoprost, bimatoprost, and travoprost), beta-adrenergic receptor antagonists (such as timolol, levobunolol, and betaxolol), alpha-2-adrenergic agonists (such as brimonidine), and carbonic anhydrase inhibitors (such as dorzolamide, brinzolamide, and acetazolamide).
The effective delivery of active agent to the posterior eye, however, remains to be a major problem in ophthalmology. Most commonly, ophthalmic pharmacotherapy relies on the topical administration of—typically liquid—formulations to the front of the eye. Most patients are well familiar with eye droppers, their use is perceived as relatively simple and convenient, and the non-invasive nature of the topical route makes it predestined for self-administration.
On the other hand, only a small fraction of a topically administered drug substance—typically less than about 5%—reaches the location where its pharmacological activity is required. Only a fraction of the volume of a formulation which is administered (which is usually about 30 to 50 μl) due to the limited volume capacity of the lacrimal sac: a significant fraction of the administered fluid volume is expelled by the blinking of the eyelids, and another fraction is taken up systemically via the nasolacrimal duct, which potentially leads to adverse drug effects. The fraction of the drug substance which does reach the posterior segment of the eye after topical administration into the fornix of the conjunctiva must first diffuse through the lacrimal film, the cornea (which represents a major barrier for most drugs), the anterior aqueous chamber, and the vitreous chamber, which diffusion path is characterised by a relatively small area, a relatively long diffusion distance, and several competing pathways which lead to drug loss. Depending on the nature of a drug substance, it may therefore be rather challenging to obtain therapeutic concentrations in the posterior segment of the eye.
In recent years, a number of alternatives to the topical route of ophthalmic delivery have been investigated. In particular, new methods, devices and compositions for intraocular and periocular administration have been proposed.
Intravitreal injections are the most direct approach to drug delivery to the posterior segment, and it is much more likely to obtain and maintain therapeutic drug levels following such type of injection than after topical delivery. A drawback of this route is that the vitreous liquid undergoes some relatively rapid turnover, so that drugs introduced into it are quickly eliminated. At the same time, intravitreal injections require the service of a specialised physician; they are clearly unfeasible for self-administration or for administration by a nurse. For patients, the mode of injection is highly uncomfortable and may be substantially painful in spite of local anaesthesia. Since many of the conditions affecting the posterior eye are of chronic or sub-chronic nature, intravitreal injection would have to be performed on a regular basis, which is even less acceptable to patients and brings about some considerable risk of iatrogenic eye infections and damage to the eye.
In order to somewhat improve patient convenience, depot formulations for intravitreal administration have been developed. These are still injected into the eye ball, or perhaps even require more extensive ophthalmic surgery to insert (and to remove, depending on the particular delivery system), but the frequency of administration can be substantially reduced. Among the proposed formulation designs are colloidal drug carriers such as liposomes, dendrimers, polymeric microparticles, and gels, but also solid implants, such as disclosed in WO 2010/062394 and WO 2008/060359. These delivery systems may provide for drug release over periods of several days, weeks, or months, depending on the nature of the drug carrier.
To avoid the inconvenience and risks associated with intravitreal injections, various forms of periocular administration have been developed as alternatives. These include in particular sub-Tenon's, subconjunctival or retrobulbar injections. This approach to drug delivery is considered safer and somewhat less invasive than intravitreal injection and also offers some potential for localised drug depots. The sub-Tenon's injection technique typically uses a short needle introduced through the superotemporal bulbar conjunctiva into the sub-Tenon's space while the patient is instructed to look inferonasally. The cannula is then advanced posteriorly along the globe in a gently sweeping motion to prevent accidental eyeball penetration until the hub reaches the conjunctival entry site, when the formulation is discharged. In a typical subconjunctival injection procedure, a needle is inserted and the medication delivered into the space between the conjunctiva and the sclera. Retrobulbar injections are frequently administered for providing local anaesthesia. A medium-short needle is inserted at the inferolateral border of the bony orbit and advanced straight back for about 1.5 cm until it has passed the equator of the globe. Then it is directed medially and upwards toward the apex of the orbit, penetrating the muscle cone delineating the retrobulbar space. Several milliliters of injection volume can be delivered to this site.
However, it is obvious that also these injection techniques, even though perhaps somewhat less distressing than intravitreal injections, are not at all convenient to patients or free of risk with respect to inadvertent bulb penetration or infection.
Thus there remains a clear need for improved delivery methods for drugs which act in the posterior segment of the eye. More specifically, there is a need for methods having a potential to achieve are more target-specific, effective delivery of therapeutic compounds to the tissues of the posterior eye. In particular, there is a need for methods which overcome one or more of the disadvantages of the currently known ophthalmic drug delivery methods. Moreover, methods are needed which are safer and more convenient than the currently practised methods. In a further aspect, there is a need for pharmaceutical compositions and kits which are useful for practising such improved methods.
It is therefore an object of the present invention to provide such improved delivery methods for active ingredients acting in the posterior eye. A further object is to provide methods which overcome one or more disadvantages that are associated with the commonly known and practised delivery methods. In a further aspect, it is an objective of the invention to provide pharmaceutical compositions which are suitable for carrying out such methods. These and further objects will become clear on the basis of the description of the invention and the patent claims.